Functional characterization of human Cd33 And Cd11b myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell linesReport as inadecuate




Functional characterization of human Cd33 And Cd11b myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines - Download this document for free, or read online. Document in PDF available to download.

Journal of Translational Medicine

, 9:90

First Online: 09 June 2011Received: 31 May 2011Accepted: 09 June 2011DOI: 10.1186-1479-5876-9-90

Cite this article as: Lechner, M.G., Megiel, C., Russell, S.M. et al. J Transl Med 2011 9: 90. doi:10.1186-1479-5876-9-90

Abstract

BackgroundTumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells MDSC. In cancer patients, MDSC accumulation correlates with increased tumor burden, but the mechanisms of MDSC induction remain poorly understood.

MethodsThis study examined the ability of human tumor cell lines to induce MDSC from healthy donor PBMC using in vitro co-culture methods. These human MDSC were then characterized for morphology, phenotype, gene expression, and function.

ResultsOf over 100 tumor cell lines examined, 45 generated canonical CD33HLA-DRLineage MDSC, with high frequency of induction by cervical, ovarian, colorectal, renal cell, and head and neck carcinoma cell lines. CD33 MDSC could be induced by cancer cell lines from all tumor types with the notable exception of those derived from breast cancer 0-9, regardless of hormone and HER2 status. Upon further examination, these and others with infrequent CD33 MDSC generation were found to induce a second subset characterized as CD11bCD33HLA-DRLineage. Gene and protein expression, antibody neutralization, and cytokine-induction studies determined that the induction of CD33 MDSC depended upon over-expression of IL-1β, IL-6, TNFα, VEGF, and GM-CSF, while CD11b MDSC induction correlated with over-expression of FLT3L and TGFβ. Morphologically, both CD33 and CD11b MDSC subsets appeared as immature myeloid cells and had significantly up-regulated expression of iNOS, NADPH oxidase, and arginase-1 genes. Furthermore, increased expression of transcription factors HIF1α, STAT3, and C-EBPβ distinguished MDSC from normal counterparts.

ConclusionsThese studies demonstrate the universal nature of MDSC induction by human solid tumors and characterize two distinct MDSC subsets: CD33HLA-DRHIF1α-STAT3 and CD11bHLA-DRC-EBPβ, which should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy.

Keywordsmyeloid-derived suppressor cells tumor immune tolerance human tumor cell lines immunomodulation cytokines hypoxia-inducible factor 1 alpha CAAAT-enhancer binding protein signal transducer and activator of transcription inflammation AbbreviationsARG-1arginase-1

C-EBP β5- and 6-: CCAAT-enhancer-binding protein

CFSEcarboxyfluorescein diacetate succinimidyl ester

c-kit Lc-kit ligand or stem cell factor

COX2cyclo-oxygenase 2

FLT3Lfms-related tyrosine kinase 3 ligand

GAPDHglyceraldehyde 3-phosphate dehydrogenase

GM-CSFgranulocyte-macrophage colony stimulating factor

HIF-1αhypoxia inducible factor-1 alpha

indoleamine 23-dioxygenase

iNOSinducible nitric oxide synthase

IFNγinterferon gamma

ILinterleukin

M-CSFmacrophage colony stimulating factor

MDSCmyeloid-derived suppressor cells

NOX2NADPH oxidase

NFκBnuclear factor kappa B

PBMCperipheral blood mononuclear cells

PGEprostaglandin E2

Tregregulatory T cells

STAT3Signal transducer and activator of transcription 3

TGFβtransforming growth factor beta

TNFαtumor necrosis factor alpha

VEGFvascular endothelial growth factor-a.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-9-90 contains supplementary material, which is available to authorized users.

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Author: Melissa G Lechner - Carolina Megiel - Sarah M Russell - Brigid Bingham - Nicholas Arger - Tammy Woo - Alan L Epstein

Source: https://link.springer.com/







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